MIT researchers have delivered a type of vaccine called a particulate vaccine to mice using a virus-mimicking scaffold made from particles of DNA instead of the usual protein particles. It not only generated a robust immune response but avoided the off-target effects sometimes seen when proteins are used.
Particulate vaccines are usually made of a scaffold of protein-based virus-like particles carrying many copies of a viral antigen. Because they mimic a natural virus, these vaccines can create a stronger immune response than traditional vaccines. They activate B cells, which produce antibodies specific to the antigen being delivered.
One potential drawback to particulate vaccines, however, is that the protein scaffolding can stimulate the production of antibodies targeting it and the antigen it’s carrying, also a protein, reducing the strength of the immune system’s response to the antigen. Additionally, because the body produces antibodies against the protein platform, it restricts its future use as a vaccine carrier, even for a different virus.
Now, researchers from MIT have developed a DNA-based scaffolding that avoids this issue, ensuring the immune system only responds to the antigen and not the platform.
“The DNA nanoparticle itself is immunogenically silent,” said Daniel Lingwood, one of the study’s corresponding authors. “If you use a protein-based platform, you get equally high-tier antibody responses to the platform and to the antigen of interest, and that can complicate repeated usage of that platform because you’ll develop high affinity immune memory against it.”
To create their scaffolds, the researchers adopted the ‘DNA origami’ technique they’d used previously, which involves folding DNA so that it mimics the structure of a virus. The technique allows the attachment of a variety of molecules, such as viral antigens, at specific locations. After attaching the receptor-binding portion of the SARS-CoV-2 spike protein to the DNA scaffold, they tested it on mice. They found the animals didn’t produce antibodies to the scaffold like they did when a protein scaffold was used, only developing antibodies to SARS-CoV-2.
“DNA, we found in this work, does not elicit antibodies that may distract away from the protein of interest,” said Mark Bathe, another corresponding author. “What you can imagine is that your B cells and immune system are being fully trained by that target antigen, and that’s what you want – for your immune system to be laser-focused on the antigen of interest.”
Unlike the T cells that are stimulated by other types of vaccines, B cells can persist for decades, providing long-term protection.
“Particulate vaccines are of great interest for many in immunology because they give you robust humoral immunity, which is antibody-based immunity, which is differentiated from the T-cell-based immunity that the mRNA vaccines seem to elicit more strongly,” Bathe said.
With their findings suggesting that DNA scaffolding is an effective alternative to protein-based platforms but without the off-target effects, the researchers are now exploring whether it could be used to simultaneously deliver different viral antigens to provide protection against a range of viruses.
“We’re interested in exploring whether we can teach the immune system to deliver higher levels of immunity against pathogens that resist conventional vaccine approaches, like flu, HIV, and SARS-CoV-2,” said Lingwood.
The study was published in the journal Nature Communications.
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